Role of Twist2 myogenic progenitor cells in adult skeletal muscle Project Summary/Abstract Adult skeletal muscle can adapt muscle mass and myofiber size under physiological and pathological conditions. Mechanical overload and hormone stimulation result in muscle growth in the form of hypertrophy and enhanced muscle strength and function. In contrast, loss of muscle mass and strength during aging and disease has profound negative consequences, leading to frailty, disability and mortality. With the world?s elderly population growing dramatically, there is an urgent need to understand the requirements for maintaining muscle homeostasis and to development therapeutic treatments for sarcopenia and cachexia. Recently, we identified a novel myogenic progenitor marked by the expression of a bHLH transcription factor Twis2 (Tw2). In adult muscle, Tw2 is expressed in interstitial cells but not mature myofibers or satellite cells. Genetic lineage tracing revealed that the Tw2+ progenitor cell population contributes specifically to type IIb/x myofibers in adult muscle during homeostasis and regeneration. Ablation of these Tw2+ cells causes type IIb fiber specific myofiber atrophy during aging. These findings highlight the unique role of Tw2+ cells in maintaining type IIb myofibers during aging. The overall goals of this project are designed to decipher the mechanisms whereby Tw2+ cells contribute to type IIb/x myofibers, to elucidate the mechanisms whereby Tw2 controls stemness and quiescence of Tw2+ cells, and to define the roles of Tw2+ cells in skeletal muscle hypertrophy and atrophy. Ultimately, we hope to use these insights to develop new strategies to therapeutically modulate muscle mass, strength and function during aging and disease.